Mutations in the tumor suppressor p53 are associated with 50% of all reported human cancers (Soussi et al., 2006). Structural instability of p53 mutants leads to partial unfolding (Bullock and Fersht, 2001) which in turn may cause p53 to form aggregates similar to those seen in amyloid diseases, such as Alzheimer's Disease (Xu et al, 2011; Levy et al, Eisenberg and Jucker, 2012). The process of p53 misfolding and aggregation results in protein inactivation, thereby removing the ‘guardian of the genome’ from its protective function (Xu et al, 2011).
In the past decades, it has been shown that several different p53 mutations, in particular those deemed to be “structural mutations,” affect p53 folding, lowering protein stability and inducing partial unfolding (Bullock and Fersht, 2001). These aberrant p53 conformations have been demonstrated in cancer biopsies by using the mutant-specific antibody PAb240 which recognizes an epitope buried in the protein core that gets solvent exposure only upon misfolding (Gannon et al, 1990). In addition, several lines of evidence have shown that fragments of p53 (Ishimaru et al, Biochemistry 2003; Silva et al, 2010; Ishimaru et al, 2009; Galea et al, 2005; Rigacci et al, 2008) as well as full-length mutant p53 (Wang et al, PNAS, 2012) undergo amyloidogenic aggregation in vitro. In addition, p53 was reported to be in the misfolded aggregated amyloid state in biopsies derived from breast cancer cases (Levy et al, 2011) as well as colon carcinomas (Xu et al, 2011) and basal cell carcinomas (Lasagna-Reeves et al, 2013).
There is a need for agents that can specifically destabilize p53 aggregates or prevent them from forming, in particular agents which are designed in a rational structure-based approach, for use in treating forms of cancer in which p53 is inactivated due to the fact that it is aberrantly folded and/or aggregated (is found inactive in fibrous form). Since about half of all diagnosed tumors present with p53 mutations, the potential for applicability of such a targeted therapeutic agent is great.